Cardiovascular disease (CVD) is the leading cause of death in the world. The staggering mortality rate is expected to increase significantly in the next ten years. In the U.S., an estimated 81 million adults will have one or more types of cardiovascular disease with an estimated total annual direct and indirect economic burden of $400 billion. Atherosclerosis is the leading cause of coronary, peripheral and carotid artery disease which are the leading causes of death in the United States. A dysfunctional endothelium is one of the initial signatures of early atherosclerosis. Its development is stimulated by multiple factors including elevated and modified low density lipoproteins (LDL), sheer stress, free radicals and hypertension. The altered endothelium induces an inflammatory response that results in formation of plaque in large and medium sized arteries. As the disease progresses, the plaque obstructs blood flow. Eventually the plaque can become unstable leading to potential life-threatening rupture and thrombosis. Current therapeutics for atherosclerotic disease generally prevent progression. A molecule that promotes plaque regression through a clearly defined novel mechanism would provide profound medical advancement in treatment of atherosclerosis. The goal of these studies is to advance such a new therapeutic toward the clinic for patients with atherosclerosis. Recently, we demonstrated that rPAI-123, a truncated isoform of plasminogen activator inhibitor-1, has anti-angiogenic activity and promotes plaque regression in hypercholesterolemic LDLR-/- ApoB48 deficient mice. The objectives of the proposed studies are: (1) to confirm, in a mouse model of atherosclerosis, that rPAI-123 stimulates plaque regression in a dose-dependent manner through the novel plasmin regulatory pathway, thereby identifying the optimal rPAI-123 dosing for future pre-clinical studies; and 2) to examine potential in vivo toxicity and side-effects associated with rPAI-123 treatment, providing the first data that optimal dosing concentrations demonstrate no or minimal side effects. PUBLIC HEALTH RELEVANCE: Current therapies for cardiovascular disease generally prevent plaque progression. This project aims to develop a therapeutic product that promotes plaque regression through a novel mechanism. Success would ultimately provide a profound medical advancement in treatment of atherosclerosis, a significant benefit to human health, and a dramatic reduction in the economic impact of the number one killer in America.